tbuckley/cabot-search huggingface dataset:
The Multifunctional Family of Mammalian Fatty Acid–Binding Proteins
Authors: Judith Storch, Betina Corsico
Journal: Annual Review of Nutrition (2023)

Fatty acid-binding proteins (FABPs) are small lipid-binding proteins abundantly expressed in tissues that are highly active in fatty acid (FA) metabolism. Ten mammalian FABPs have been identified, with tissue-specific expression patterns and highly conserved tertiary structures. FABPs were initially studied as intracellular FA transport proteins. Further investigation has demonstrated their participation in lipid metabolism, both directly and via regulation of gene expression, and in signaling within their cells of expression. There is also evidence that they may be secreted and have functional impact via the circulation. It has also been shown that the FABP ligand binding repertoire extends beyond long-chain FAs and that their functional properties also involve participation in systemic metabolism. This article reviews the present understanding of FABP functions and their apparent roles in disease, particularly metabolic and inflammation-related disorders and cancers.
Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer: MAINTAIN Trial
Authors: Kevin Kalinsky, Melissa K. Accordino, Codruta Chiuzan, Prabhjot S. Mundi, Elizabeth Sakach, Claire Sathe, Heejoon Ahn, Meghna S. Trivedi, Yelena Novik, Amy Tiersten, George Raptis, Lea N. Baer, Sun Y. Oh, Amelia B. Zelnak, Kari B. Wisinski, Eleni Andreopoulou, William J. Gradishar, Erica Stringer-Reasor, Sonya A. Reid, Anne O'Dea, Ruth O'Regan, Katherine D. Crew, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2023)

PURPOSE Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.
Intermetastatic and Intrametastatic Heterogeneity Shapes Adaptive Therapy Cycling Dynamics
Authors: Jill Gallaher, Maximilian Strobl, Jeffrey West, Robert Gatenby, Jingsong Zhang, Mark Robertson-Tessi, Alexander R.A. Anderson
Journal: Cancer Research (2023)

Adaptive therapies that alternate between drug applications and drug-free vacations can exploit competition between sensitive and resistant cells to maximize the time to progression. However, optimal dosing schedules depend on the properties of metastases, which are often not directly measurable in clinical practice. Here, we proposed a framework for estimating features of metastases through tumor response dynamics during the first adaptive therapy treatment cycle. Longitudinal prostate-specific antigen (PSA) levels in 16 patients with metastatic castration-resistant prostate cancer undergoing adaptive androgen deprivation treatment were analyzed to investigate relationships between cycle dynamics and clinical variables such as Gleason score, the change in the number of metastases over a cycle, and the total number of cycles over the course of treatment. The first cycle of adaptive therapy, which consists of a response period (applying therapy until 50% PSA reduction), and a regrowth period (removing treatment until reaching initial PSA levels), delineated several features of the computational metastatic system: larger metastases had longer cycles; a higher proportion of drug-resistant cells slowed the cycles; and a faster cell turnover rate sped up drug response time and slowed regrowth time. The number of metastases did not affect cycle times, as response dynamics were dominated by the largest tumors rather than the aggregate. In addition, systems with higher intermetastasis heterogeneity responded better to continuous therapy and correlated with dynamics from patients with high or low Gleason scores. Conversely, systems with higher intrametastasis heterogeneity responded better to adaptive therapy and correlated with dynamics from patients with intermediate Gleason scores.Multiscale mathematical modeling combined with biomarker dynamics during adaptive therapy helps identify underlying features of metastatic cancer to inform treatment decisions.
Cytolytic CD8 <sup>+</sup> T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes
Authors: David R. Collins, Julia Hitschfel, Jonathan M. Urbach, Geetha H. Mylvaganam, Ngoc L. Ly, Umar Arshad, Zachary J. Racenet, Adrienne G. Yanez, Thomas J. Diefenbach, Bruce D. Walker
Journal: Science Immunology (2023)

Follicular CD8+ T cells (fCD8) mediate surveillance in lymph node (LN) germinal centers against lymphotropic infections and cancers, but the precise mechanisms by which these cells mediate immune control remain incompletely resolved. To address this, we investigated functionality, clonotypic compartmentalization, spatial localization, phenotypic characteristics, and transcriptional profiles of LN-resident virus-specific CD8+ T cells in persons who control HIV without medications. Antigen-induced proliferative and cytolytic potential consistently distinguished spontaneous controllers from noncontrollers. T cell receptor analysis revealed complete clonotypic overlap between peripheral and LN-resident HIV-specific CD8+ T cells. Transcriptional analysis of LN CD8+ T cells revealed gene signatures of inflammatory chemotaxis and antigen-induced effector function. In HIV controllers, the cytotoxic effectors perforin and granzyme B were elevated among virus-specific CXCR5+ fCD8s proximate to foci of HIV RNA within germinal centers. These results provide evidence consistent with cytolytic control of lymphotropic infection supported by inflammatory recruitment, antigen-specific proliferation, and cytotoxicity of fCD8s.
Is a lack of diversity among clinical practice guideline authors contributing to health inequalities for patients?
Authors: Julie K. Silver
Journal: BMJ (2023)

Is a lack of diversity among clinical practice guideline authors contributing to health inequalities for patients?Julie K. Silver associate professorassociate chair Clinical practice guidelines and other types of guidance documents are among the most important evidence based publications in medicine.Many clinical practice guidelines are disseminated beyond the borders of the country that produced them, and affect access to care, diagnostic work-up, and treatment interventions for billions of people worldwide.This is especially true if they are published or endorsed by influential organisations such as professional societies in the United States, United Kingdom, European Union, and Canada.
PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance
Authors: Mandy van Gulijk, Anneloes van Krimpen, Sjoerd Schetters, Mike Eterman, Marit van Elsas, Joanne Mankor, Larissa Klaase, Marjolein de Bruijn, Menno van Nimwegen, Tim van Tienhoven, Wilfred van Ijcken, Louis Boon, Johan van der Schoot, Martijn Verdoes, Ferenc Scheeren, Sjoerd H. van der Burg, Bart N. Lambrecht, Ralph Stadhouders, Floris Dammeijer, Joachim Aerts, Thorbald van Hall
Journal: Science Immunology (2023)

Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (Treg cells) in αPD-L1 therapy-resistant solid tumor-bearing mice. Treg cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating Treg cells in human patients with skin cancer, and in patients with non-small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1-induced PD-1+ Treg cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of Treg cells, resulting in therapy resistance, suggesting that Treg cell targeting is an important adjunct strategy to enhance therapeutic efficacy.
Bulk T‐cell receptor sequencing confirms clonality in pediatric eosinophilic esophagitis and identifies a food‐specific repertoire
Authors: Rethavathi Janarthanam, Fei Li Kuang, Angelika Zalewski, Katie Amsden, Ming‐Yu Wang, Lorena Ostilla, Kaitlyn Keeley, Ikuo Hirano, Amir Kagalwalla, Barry K. Wershil, Nirmala Gonsalves, Joshua B. Wechsler
Journal: Allergy (2023)

Eosinophilic esophagitis (EoE) involves a chronic immune-mediated response to dietary antigens. Recent work identifies T-cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food-specific T-cell repertoire. We sought to confirm T-cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers.
The Role of Artificial Intelligence in Deciphering Diet–Disease Relationships: Case Studies
Authors: Yotam Cohen, Rafael Valdés-Mas, Eran Elinav
Journal: Annual Review of Nutrition (2023)

Modernization of society from a rural, hunter-gatherer setting into an urban and industrial habitat, with the associated dietary changes, has led to an increased prevalence of cardiometabolic and additional noncommunicable diseases, such as cancer, inflammatory bowel disease, and neurodegenerative and autoimmune disorders. However, while dietary sciences have been rapidly evolving to meet these challenges, validation and translation of experimental results into clinical practice remain limited for multiple reasons, including inherent ethnic, gender, and cultural interindividual variability, among other methodological, dietary reporting-related, and analytical issues. Recently, large clinical cohorts with artificial intelligence analytics have introduced new precision and personalized nutrition concepts that enable one to successfully bridge these gaps in a real-life setting. In this review, we highlight selected examples of case studies at the intersection between diet-disease research and artificial intelligence. We discuss their potential and challenges and offer an outlook toward the transformation of dietary sciences into individualized clinical translation.
Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial
Authors: Jun-Dong Wu, Jing-Xin Li, Jian Liu, Hao-Meng Wang, Guang-Hui Zhou, Jin Li, Dou Wu, Xiang Chen, Yan Feng, Xiao-Yuan Qi, Xue Wang, Jin-Bo Gou, Tie-Liang Ma, Xiao-Yun Yang, Li-Feng Xu, Peng Wan, Tao Zhu, Zhong-Fang Wang, Feng-Cai Zhu, Ying Wang, Xiaomin Ma
Journal: The Lancet Infectious Diseases (2023)
Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation
Authors: Sally J Singh, Molly M Baldwin, Enya Daynes, Rachael A Evans, Neil J Greening, R Gisli Jenkins, Nazir I Lone, Hamish McAuley, Puja Mehta, Joseph Newman, Petr Novotny, David J F Smith, Stefan Stanel, Mark Toshner, Christopher E Brightling
Journal: The Lancet Respiratory Medicine (2023)
RNA binding proteins in senescence: A potential common linker for age-related diseases?
Authors: Angelica Varesi, Lucrezia Irene Maria Campagnoli, Annalisa Barbieri, Lorenzo Rossi, Giovanni Ricevuti, Ciro Esposito, Salvatore Chirumbolo, Nicoletta Marchesi, Alessia Pascale
Journal: Ageing Research Reviews (2023)
Effect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis
Authors: Michelle Casey, Claudie Gabillard-Lefort, Oisín F McElvaney, Oliver J McElvaney, Tomás Carroll, Ronan C Heeney, Cedric Gunaratnam, Emer P Reeves, Mark P Murphy, Noel G McElvaney
Journal: Thorax (2023)

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)−1β and IL-8 in sputum, accompanied by decreased Pseudomonas burden and restoration of secretory leukoprotease inhibitor levels. Once treated with ETI, all airway inflammatory markers studied in PWCF had reduced to levels found in matched non-CF bronchiectasis controls. In PWCF with advanced disease, ETI resulted in decreased plasma concentrations of IL-6, C-reactive protein and soluble TNF receptor one as well as normalisation of levels of the acute phase protein, alpha-1 antitrypsin. These data clarify the immunomodulatory effects of ETI and underscore its role as a disease modifier.
Risk factors for poorer respiratory outcomes in adolescents and young adults born preterm
Authors: Elizabeth F Smith, Naomi R Hemy, Graham L Hall, Andrew C Wilson, Conor P Murray, Shannon J Simpson
Journal: Thorax (2023)

The respiratory outcomes for adult survivors of preterm birth in the postsurfactant era are wide-ranging with prognostic factors, especially those encountered after the neonatal period, poorly understood.
Periostin+ Stromal Cells Guide Lymphovascular Invasion by Cancer Cells
Authors: Jamie L. Null, Dae Joong Kim, James V. McCann, Patcharin Pramoonjago, Jay W. Fox, Jianhao Zeng, Pankaj Kumar, Lincy Edatt, Chad V. Pecot, Andrew C. Dudley
Journal: Cancer Research (2023)

Abstract Cancer cell dissemination to sentinel lymph nodes is associated with poor patient outcomes, particularly in breast cancer. The process by which cancer cells egress from the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells, including cancer-associated fibroblasts (CAF). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, as periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labeling and ablation to lineage trace periostin+ cells and characterize their functions during tumor growth and metastasis. Periostin-expressing CAFs were spatially found at periductal and perivascular margins, were enriched at lymphatic vessel peripheries, and were differentially activated by highly metastatic cancer cells versus poorly metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site that promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes. Significance: Highly metastatic breast cancer cells activate a population of periostin-expressing CAFs that remodel the extracellular matrix to promote escape of cancer cells into lymphatic vessels and drive colonization of proximal lymph nodes.
The HDAC2-SP1 Axis Orchestrates Protumor Macrophage Polarization
Authors: Xiang Zheng, Poonam Sarode, Andreas Weigert, Kati Turkowski, Prakash Chelladurai, Stefan Günther, Carsten Kuenne, Hauke Winter, Albrecht Stenzinger, Simone Reu, Friedrich Grimminger, Thorsten Stiewe, Werner Seeger, Soni Savai Pullamsetti, Rajkumar Savai
Journal: Cancer Research (2023)

Tumor-associated macrophages (TAM), including antitumor M1-like TAMs and protumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key in controlling macrophage fate in the heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of HDAC2-overexpressing M2-like TAMs to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage phenotype, migration, and signaling pathways related to interleukins, chemokines, cytokines, and T-cell activation. In coculture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs resulted in reduced proliferation and migration, increased apoptosis of cancer cell lines and primary lung cancer cells, and attenuated endothelial cell tube formation. HDAC2 regulated the M2-like TAM phenotype via acetylation of histone H3 and transcription factor SP1. Myeloid cell-specific deletion of Hdac2 and pharmacologic inhibition of class I HDACs in four different murine lung cancer models induced the switch from M2-like to M1-like TAMs, altered infiltration of CD4+ and CD8+ T cells, and reduced tumor growth and angiogenesis. TAM-specific HDAC2 expression may provide a biomarker for lung cancer stratification and a target for developing improved therapeutic approaches.HDAC2 inhibition reverses the protumor phenotype of macrophages mediated by epigenetic modulation induced by the HDAC2-SP1 axis, indicating a therapeutic option to modify the immunosuppressive tumor microenvironment.
Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants
Authors: Dhruv Chachad, Lalit R. Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M. Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano
Journal: Cancer Research (2023)

Abstract Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared with p53-null mice, suggesting GOF. RNA sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. In addition, analyses of p53R248W chromatin immunoprecipitation peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53. Significance: The p53 DNA binding domain contact mutant p53R245W, but not the structural mutant p53R172H, interacts with KLF15 to drive metastasis in somatic osteosarcoma, providing a potential vulnerability in tumors expressing p53R245W mutation.
Higher SARS-CoV-2 detection of oropharyngeal compared with nasopharyngeal or saliva specimen for molecular testing: a multicentre randomised comparative accuracy study
Authors: Tobias Todsen, Martin G Tolsgaard, Thomas Benfield, Fredrik Folke, Kathrine K Jakobsen, Niels Tobias Gredal, Annette K Ersbøll, Christian von Buchwald, Nikolai Kirkby
Journal: Thorax (2023)

Background Testing is critical for detecting SARS-CoV-2 infection, but the best sampling method remains unclear. Objectives To determine whether nasopharyngeal swab (NPS), oropharyngeal swab (OPS) or saliva specimen collection has the highest detection rate for SARS-CoV-2 molecular testing. Methods We conducted a randomised clinical trial at two COVID-19 outpatient test centres where NPS, OPS and saliva specimens were collected by healthcare workers in different orders for reverse transcriptase PCR testing. The SARS-CoV-2 detection rate was calculated as the number positive by a specific sampling method divided by the number in which any of the three sampling methods was positive. As secondary outcomes, test-related discomfort was measured with an 11-point numeric scale and cost-effectiveness was calculated. Results Among 23 102 adults completing the trial, 381 (1.65%) were SARS-CoV-2 positive. The SARS-CoV-2 detection rate was higher for OPSs, 78.7% (95% CI 74.3 to 82.7), compared with NPSs, 72.7% (95% CI 67.9 to 77.1) (p=0.049) and compared with saliva sampling, 61.9% (95% CI 56.9 to 66.8) (p&lt;0.001). The discomfort score was highest for NPSs, at 5.76 (SD, 2.52), followed by OPSs, at 3.16 (SD 3.16) and saliva samples, at 1.03 (SD 18.8), p&lt;0.001 between all measurements. Saliva specimens were associated with the lowest cost, and the incremental costs per detected SARS-CoV-2 infection for NPSs and OPSs were US$3258 and US$1832, respectively. Conclusions OPSs were associated with higher SARS-CoV-2 detection and lower test-related discomfort than NPSs for SARS-CoV-2 testing. Saliva sampling had the lowest SARS-CoV-2 detection but was the least costly strategy for mass testing. Trial registration number NCT04715607 .